S276: TRANSFERRIN RECEPTOR 2 TARGETING AMELIORATES DIFFERENT FORMS OF ANEMIA CAUSED BY CHRONIC INFLAMMATION
Authors: V. Olivari, M. R. Lidonnici, E. Tanzi, S. M. Di Modica, F. Tiboni, L. Silvestri, G. Ferrari, A. Nai
Journal: HemaSphere (2022)

Background: Anemia is a common complication of chronic inflammation. It is caused by an increased production of the iron-regulatory hormone hepcidin, that leads to iron restriction, and by decreased erythrocytes sensitivity to erythropoietin (EPO) stimulation. Anemia of Chronic Kidney Disease (CKD) is a form of anemia of inflammation, in which progressive renal damage, besides causing systemic inflammation and iron deficiency, impairs erythropoietin (EPO) production. Current EPO-based treatments may cause off-target effects on long term and often require iron supplementation, mainly for CKD. Transferrin Receptor 2 (TFR2) modulates iron homeostasis in the liver, contributing to the transcriptional activation of hepcidin, and acts as a brake of EPO signaling in erythroid cells. Its selective deletion in the bone marrow (BM, Tfr2BMKO) enhances erythropoiesis both in wild-type and thalassemic mice. Aims: We investigated whether Tfr2 targeting might represent a therapeutic option for different forms of anemia, able to enhance erythropoiesis in chronic inflammation and simultaneously increase iron availability in CKD. Methods: Chronic sterile inflammation was induced by weekly subcutaneous injection of turpentine oil (100ul/20g body weight for 3 weeks) in Tfr2BMKO mice. Mice were sacrificed 2 or 14 days after the last injection. CKD was induced feeding Tfr2BMKO mice an adenine-rich diet for 8 weeks. The same protocol was applied also in germline Tfr2 deficient (Tfr2-ko) animals to simultaneously inactivate erythroid and hepatic Tfr2. Complete blood count was periodically determined, and a complete phenotypic analysis was performed at sacrifice. Results: Chronically inflamed Tfr2BMKO mice maintained red blood cell count and hemoglobin levels higher than controls for the entire 5-week-long timespan, despite comparable inflammation. In CKD mice, BM-specific Tfr2 inactivation enhanced erythropoiesis and delayed anemia until iron availability was sufficient: indeed, hemoglobin came back to control values at the end of the protocol. The drop in hemoglobin levels was prevented in Tfr2-ko mice, in which iron supply is increased. Renal damage was comparable among the experimental groups, excluding a differential effect of the diet. Of note, BM-specific Tfr2 deletion boosted erythropoiesis and activated EPO-EPOR pathway without affecting EPO levels both in CKD and turpentine mice. Summary/Conclusion: We proved that erythroid Tfr2 targeting ameliorates hematological parameters in murine models of anemia of inflammation and anemia of CKD. The beneficial effect is achieved enhancing erythroid EPO responsiveness, without affecting EPO levels per se. For this reason, an approach based on erythroid TFR2 targeting would avoid the side effects of the available therapies. Moreover, we demonstrated that the concomitant inhibition of hepatic and erythroid Tfr2 in anemia of CKD would represent a therapeutic opportunity to simultaneously increase iron availability and erythroid responsiveness in a balanced manner. Overall, our results prove that TFR2 targeting may represent a tunable therapeutic approach for different forms of anemia.